A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

Abstract

Purpose: Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents.Experimental design: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules.Results: The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 AE 10.8) compared with small molecules (2.1 AE 1.1; P ¼ 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 AE 2.9) compared with small molecules (4.1 AE 1.5; P ¼ 0.008).Conclusions: The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity.

Assembly of kafirin/carboxymethyl chitosan nanoparticles to enhance the cellular uptake of curcumin

“…In an attempt to address this problem, researchers are using nanoparticles as the delivery vehicles (Caron, Morgan, Zamboni, & Zamboni, 2013;Chen, Sonaje, Chen, & Sung, 2011;Crosera et al, 2009). The enhanced bioavailabilities of these bioactives through nanoencapsulation are excepted due to the protection against biochemical degradation (Jia, 2005), increased interact surface area with the biological support (Kawashima, 2001), readily uptake through the epithelial lining via paracellular or transcellular transport, and diverse biological properties such as bioadhesion and targeting (Galindo-Rodriguez, Allemann, Fessi, & Doelker, 2005).…”

Physiologically Based Pharmacokinetic Modeling of Nanoparticles

“…As the MPS plays a central role in nanoparticle disposition, the PK of nanoparticles is more variable than that of their small molecule counterparts. 77 A meta-analysis of nine liposomal anticancer agents showed that liposomes have a higher inter-patient variability than their small molecule counterparts. 78 The inter-patient variability in exposure (plasma AUC) of PEGylated liposomal CKD602 can be as high as 20- to 100-fold.…”

Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

“…The lack of proper scaling can further be compounded when attempting to determine CMA agent starting doses in phase I clinical trials. While the optimal species remains unclear, the maximum recommended starting dose (MRSD) is determined based on the no observed adverse effect levels (NOAELs) in the tested animal species, including the most sensitive species . A recent review evaluated the design, progression, and outcomes of phase I studies of CMAs compared with SM anticancer agents in patients with advanced solid tumors, including: the basis for starting dose, number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose .…”

“…While the optimal species remains unclear, the maximum recommended starting dose (MRSD) is determined based on the no observed adverse effect levels (NOAELs) in the tested animal species, including the most sensitive species . A recent review evaluated the design, progression, and outcomes of phase I studies of CMAs compared with SM anticancer agents in patients with advanced solid tumors, including: the basis for starting dose, number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose . Of greatest impact, the average ratio of MTD to starting dose in these studies were significantly greater and more variable for CMAs compared to SMs (13.9 ± 10.8 versus 2.1 ± 1.1, p = 0.005) .…”